Retinal transplantation represents a promising approach for restoring sight to aging patients with degenerative diseases of the retina associated with loss of photoreceptors and partial or complete blindness (age-related macular degeneration, retinitis pigmentosa). Indeed, a number of studies show that partial recovery of visual functions can be achieved by retinal transplantation. However, a recent study in our laboratory shows that immune-mediated rejection represents a major barrier to long-term survival of transplanted retinas (Anosova et al. J. Clin. Invest, 2001). We demonstrated that recipient CD4+ T cells recognizing donor MHC class II proteins via direct allorecognition initiate the immune response to allogeneic retinas. Most importantly, we showed that this response causes accelerated deterioration of retinal allotransplants. Our and other laboratories have developed novel techniques to block direct alloresponses and prolong transplant survival. Our goal is to block the direct T cell alloresponse in rd/rd mice with progressive loss of photoreceptors and retinal degeneration (C3H/HeJ rd/rd.). To achieve this, we p{an: la) To suppress direct anti-donor immune responses in retinal grafted C3H/HeJ rd/rd mice: We will block alloreactive direct T cell responses using T cell costimulation blockade We wilt prevent direct alloresponses using MHC gene therapy lb) To evaluate visual functions (electrophysiology and behavior) after blocking anti-donor immune response in retinal-grafted C3H/HeJ rd/rd mice We will measure electrophysiological functions in retinal grafts (response to light: Retinal ganglion cell (GRC) responses and electroretinograms (ERGs)). We will investigate the restoration of visually mediated behavior in retinal-grafted mice. Our study will set the path for the choice of appropriate immune therapies in retinal transplantation for patients with age-related degenerative diseases of the retina. The overall health relevance of the proposed research is that transplantation of cells and tissues of the nervous system is currently being developed in the United States for patients with age-related neurodegenerative diseases including Alzheimer disease, Multiple Sclerosis and Macular Degeneration. Our project is to reduce the immunogenicity of these neural transplants and design treatments to prevent/block their immune-mediated destruction.